The Myc oncoprotein network modulates cell cycle progression, growth, differentiation, apoptosis, and genomic integrity. De-regulation of c-Myc, the prototype member of the family, occurs commonly in many malignancies and is invariably associated with genomic instability and secondary mutations. Understanding the molecular basis for c-Myc's activities will involve characterizing proteins with which it interacts, characterizing the gene products under its control, and determining their roles in mediating c-Myc's multiple phenotypes. Toward the first of these ends, we have recently identified a novel protein, PAG, or peroxiredoxin 1, that interacts with the transcriptional activation domain of c-Myc. PAG inhibits transformation by c-Myc while preserving or even enhancing its other activities. PAG protects cells against oxidative DNA damage and is a tumor suppressor. We have also identified a new transcriptional target for c-Myc, termed MT-MC1, whose over-expression mimics many of the phenotypic properties of c-Myc, including the ability to transform, to alter cellular morphology, to promote apoptosis, to inhibit differentiation, to promote genomic instability, and to regulate some c-Myc target genes. Many of MT-MC1's properties are c-Myc-independent. MT-MC1 thus plays a critical and proximal role in the c-Myc signaling pathway by virtue of its ability to regulate multiple c-Myc functions. Recent evidence also suggests a functional and biochemical connection among c-Myc, PAG, and MT-MC1 with regard to their ability to modulate the response of cells to oxidative stress. Damaged DNA arising from such stress may be a major contributor to tumor generation and/or evolution. In the First Specific Aim of this application, we propose further studies with PAG. These include defining its c-Myc-independent functions, identifying novel proteins with which it interacts, defining the regions necessary for its interaction with c- Myc, and further characterizing a PAG knockout mouse strain. These mice will be used in conjunction with a novel inducible in vivo model of c-Myc-mediated tumorigenesis, regression, and spontaneous recurrence (Tet-Myc mice). In the Second Specific Aim, we propose further studies with MT-MC1. We will examine the effect of MT-MC1 in primary cells, will identify novel MT-MC1-interacting proteins, will further investigate the modular nature of MT-MC1's multiple functions, and will create a conditional MT-MC1 """"""""knockout"""""""" mouse strain. Crosses between these animals and either PAG-/- mice or Tet-Myc mice will help to further define in vivo the proposed three-way connection among c-Myc, PAG, and MT-MC1.
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